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Modeling Neurodevelopmental Disorders Using Human Pluripotent Stem Cells

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Abstract

Neurodevelopmental disorders (NDs) are impairments that affect the development and growth of the brain and the central nervous system during embryonic and early postnatal life. Genetically manipulated animals have contributed greatly to the advancement of ND research, but many of them differ considerably from the human phenotype. Cellular in vitro models are also valuable, but the availability of human neuronal cells is limited and their lifespan in culture is short. Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, comprise a powerful tool for studying developmentally regulated diseases, including NDs. We reviewed all recent studies in which hPSCs were used as in vitro models for diseases and syndromes characterized by impairment of neurogenesis or synaptogenesis leading to intellectual disability and delayed neurodevelopment. We analyzed their methodology and results, focusing on the data obtained following in vitro neural differentiation and gene expression and profiling of the derived neurons. Electrophysiological recording of action potentials, synaptic currents and response to neurotransmitters is pivotal for validation of the neuronal fate as well as for assessing phenotypic dysfunctions linked to the disease in question. We therefore focused on the studies which included electrophysiological recordings on the in vitro-derived neurons. Finally, we addressed specific issues that are critical for the advancement of this area of research, specifically in providing a reliable human pre-clinical research model and drug screening platform.

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References

  1. Goldstein, S., & Reynolds, C. R. (1999). Handbook of neurodevelopmental and genetic disorders in children (p. 602). New York: Guilford Press. xvi.

    Google Scholar 

  2. Clegg, J., Gillott, A., & Jones, J. (2013). Conceptual issues in neurodevelopmental disorders: lives out of synch. Curr Opin Psychiatry, 26(3), 289–94.

    PubMed  Google Scholar 

  3. Shinoda, Y., Sadakata, T., & Furuichi, T. (2013). Animal models of autism spectrum disorder (ASD): a synaptic-level approach to autistic-like behavior in mice. Exp Anim, 62(2), 71–8.

    CAS  PubMed  Google Scholar 

  4. Gadad, B. S., Hewitson, L., Young, K. A., & German, D. C. (2013). Neuropathology and Animal Models of Autism: Genetic and Environmental Factors. Autism Res Treat, 2013, 731935.

    PubMed Central  PubMed  Google Scholar 

  5. Lu, J., Delli-Bovi, L.C., Hecht, J., Folkerth, R., and Sheen, V.L. (2011). Generation of neural stem cells from discarded human fetal cortical tissue. J Vis Exp, (51).

  6. Verwer, R. W., Hermens, W. T., Dijkhuizen, P., ter Brake, O., Baker, R. E., Salehi, A., et al. (2002). Cells in human postmortem brain tissue slices remain alive for several weeks in culture. FASEB J, 16(1), 54–60.

    CAS  PubMed  Google Scholar 

  7. Mayer, E. J., Carter, D. A., Ren, Y., Hughes, E. H., Rice, C. M., Halfpenny, C. A., et al. (2005). Neural progenitor cells from postmortem adult human retina. Br J Ophthalmol, 89(1), 102–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–7.

    CAS  PubMed  Google Scholar 

  9. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–72.

    CAS  PubMed  Google Scholar 

  10. Peitz, M., Jungverdorben, J., & Brustle, O. (2013). Disease-specific iPS cell models in neuroscience. Curr Mol Med, 13(5), 832–41.

    CAS  PubMed  Google Scholar 

  11. Nakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K., et al. (2012). Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell, 10(6), 771–85.

    CAS  PubMed  Google Scholar 

  12. Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373–9.

    CAS  PubMed  Google Scholar 

  13. Little, J. (2000). Epidemiology of neurodevelopmental disorders in children. Prostaglandins Leukot Essent Fatty Acids, 63(1–2), 11–20.

    CAS  PubMed  Google Scholar 

  14. Petersen, M. C., Kube, D. A., & Palmer, F. B. (1998). Classification of developmental delays. Semin Pediatr Neurol, 5(1), 2–14.

    CAS  PubMed  Google Scholar 

  15. Korkmaz, B. (2011). Theory of mind and neurodevelopmental disorders of childhood. Pediatr Res, 69(5 Pt 2), 101R–8R.

    PubMed  Google Scholar 

  16. Barkovich, A. J., Guerrini, R., Kuzniecky, R. I., Jackson, G. D., & Dobyns, W. B. (2012). A developmental and genetic classification for malformations of cortical development: update 2012. Brain, 135(Pt 5), 1348–69.

    PubMed Central  PubMed  Google Scholar 

  17. Nowakowski, R. S., & Hayes, N. L. (1999). CNS development: an overview. Dev Psychopathol, 11(3), 395–417.

    CAS  PubMed  Google Scholar 

  18. Stiles, J., & Jernigan, T. L. (2010). The basics of brain development. Neuropsychol Rev, 20(4), 327–48.

    PubMed Central  PubMed  Google Scholar 

  19. Hrvoj-Mihic, B., Bienvenu, T., Stefanacci, L., Muotri, A. R., & Semendeferi, K. (2013). Evolution, development, and plasticity of the human brain: from molecules to bones. Front Hum Neurosci, 7, 707.

    PubMed Central  PubMed  Google Scholar 

  20. Chaboub, L. S., & Deneen, B. (2012). Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci, 34(5), 379–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Webster, H., & Astrom, K. E. (2009). Gliogenesis: historical perspectives, 1839–1985. Adv Anat Embryol Cell Biol, 202, 1–109.

    PubMed  Google Scholar 

  22. Sequerra, E. B., Costa, M. R., Menezes, J. R., & Hedin-Pereira, C. (2013). Adult neural stem cells: plastic or restricted neuronal fates? Development, 140(16), 3303–9.

    CAS  PubMed  Google Scholar 

  23. Bellenchi, G. C., Volpicelli, F., Piscopo, V., Perrone-Capano, C., & di Porzio, U. (2013). Adult neural stem cells: an endogenous tool to repair brain injury? J Neurochem, 124(2), 159–67.

    CAS  PubMed  Google Scholar 

  24. Bourgeois, J. P. (1997). Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex. Acta Paediatr Suppl, 422, 27–33.

    CAS  PubMed  Google Scholar 

  25. Berlucchi, G., & Buchtel, H. A. (2009). Neuronal plasticity: historical roots and evolution of meaning. Exp Brain Res, 192(3), 307–19.

    CAS  PubMed  Google Scholar 

  26. van Loo, K. M., & Martens, G. J. (2007). Genetic and environmental factors in complex neurodevelopmental disorders. Curr Genomics, 8(7), 429–44.

    PubMed Central  PubMed  Google Scholar 

  27. Pichichero, M. E. (2009). The PANDAS syndrome. Adv Exp Med Biol, 634, 205–16.

    PubMed  Google Scholar 

  28. Schendel, D. E. (2001). Infection in pregnancy and cerebral palsy. J Am Med Womens Assoc, 56(3), 105–8.

    CAS  PubMed  Google Scholar 

  29. Osterhues, A., Ali, N. S., & Michels, K. B. (2013). The role of folic acid fortification in neural tube defects: a review. Crit Rev Food Sci Nutr, 53(11), 1180–90.

    CAS  PubMed  Google Scholar 

  30. Volpe, P., Campobasso, G., De Robertis, V., & Rembouskos, G. (2009). Disorders of prosencephalic development. Prenat Diagn, 29(4), 340–54.

    CAS  PubMed  Google Scholar 

  31. Schuurmans, C., & Kurrasch, D. M. (2013). Neurodevelopmental consequences of maternal distress: what do we really know? Clin Genet, 83(2), 108–17.

    CAS  PubMed  Google Scholar 

  32. Manning, M. A., & Eugene Hoyme, H. (2007). Fetal alcohol spectrum disorders: a practical clinical approach to diagnosis. Neurosci Biobehav Rev, 31(2), 230–8.

    CAS  PubMed  Google Scholar 

  33. Sankar, C., & Mundkur, N. (2005). Cerebral palsy-definition, classification, etiology and early diagnosis. Indian J Pediatr, 72(10), 865–8.

    PubMed  Google Scholar 

  34. Ryan, S. G. (1999). Genetic susceptibility to neurodevelopmental disorders. J Child Neurol, 14(3), 187–95.

    CAS  PubMed  Google Scholar 

  35. Skuse, D. H. (1997). Genetic factors in the etiology of child psychiatric disorders. Curr Opin Pediatr, 9(4), 354–60.

    CAS  PubMed  Google Scholar 

  36. Schendel, D., Rice, C., & Cunniff, C. (2010). The contribution of rare diseases to understanding the epidemiology of neurodevelopmental disabilities. Adv Exp Med Biol, 686, 433–53.

    PubMed  Google Scholar 

  37. Coe, B. P., Girirajan, S., & Eichler, E. E. (2012). A genetic model for neurodevelopmental disease. Curr Opin Neurobiol, 22(5), 829–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013). Somatic mutation, genomic variation, and neurological disease. Science, 341(6141), 1237758.

    PubMed Central  PubMed  Google Scholar 

  39. Fernandes, A. M., Meletti, T., Guimaraes, R., Stelling, M. P., Marinho, P. A., Valladao, A. S., et al. (2010). Worldwide survey of published procedures to culture human embryonic stem cells. Cell Transplant, 19(5), 509–23.

    CAS  PubMed  Google Scholar 

  40. Frumkin, T., Malcov, M., Telias, M., Gold, V., Schwartz, T., Azem, F., et al. (2010). Human embryonic stem cells carrying mutations for severe genetic disorders. Vitro Cell Dev Biol Anim, 46(3–4), 327–36.

    Google Scholar 

  41. Vazin, T., & Freed, W. J. (2010). Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor Neurol Neurosci, 28(4), 589–603.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Crocco, M. C., Fratnz, N., & Bos-Mikich, A. (2013). Substrates and supplements for hESCs: a critical review. J Assist Reprod Genet, 30(3), 315–23.

    PubMed Central  PubMed  Google Scholar 

  43. Nichols, J., & Smith, A. (2012). Pluripotency in the embryo and in culture. Cold Spring Harb Perspect Biol, 4(8), a008128.

    PubMed Central  PubMed  Google Scholar 

  44. Deb, K. D., Jayaprakash, A. D., Sharma, V., & Totey, S. (2008). Embryonic stem cells: from markers to market. Rejuvenation Res, 11(1), 19–37.

    CAS  PubMed  Google Scholar 

  45. Ameen, C., Strehl, R., Bjorquist, P., Lindahl, A., Hyllner, J., & Sartipy, P. (2008). Human embryonic stem cells: current technologies and emerging industrial applications. Crit Rev Oncol Hematol, 65(1), 54–80.

    PubMed  Google Scholar 

  46. Unger, C., Skottman, H., Blomberg, P., Dilber, M. S., & Hovatta, O. (2008). Good manufacturing practice and clinical-grade human embryonic stem cell lines. Hum Mol Genet, 17(R1), R48–53.

    CAS  PubMed  Google Scholar 

  47. Strelchenko, N., & Verlinsky, Y. (2006). Embryonic stem cells from morula. Methods Enzymol, 418, 93–108.

    CAS  PubMed  Google Scholar 

  48. Ben-Yosef, D., Amit, A., Malcov, M., Frumkin, T., Ben-Yehudah, A., Eldar, I., et al. (2012). Female sex bias in human embryonic stem cell lines. Stem Cells Dev, 21(3), 363–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Biancotti, J. C., & Lavon, N. (2012). Derivation, expansion, and characterization of human embryonic stem cell lines from aneuploid embryos. Methods Mol Biol, 873, 163–78.

    CAS  PubMed  Google Scholar 

  50. Ben-Yehudah, A., Malcov, M., Frumkin, T., & Ben-Yosef, D. (2012). Mutated human embryonic stem cells for the study of human genetic disorders. Methods Mol Biol, 873, 179–207.

    CAS  PubMed  Google Scholar 

  51. Dvash, T., Ben-Yosef, D., & Eiges, R. (2006). Human embryonic stem cells as a powerful tool for studying human embryogenesis. Pediatr Res, 60(2), 111–7.

    PubMed  Google Scholar 

  52. Dvash, T., & Benvenisty, N. (2004). Human embryonic stem cells as a model for early human development. Best Pract Res Clin Obstet Gynaecol, 18(6), 929–40.

    PubMed  Google Scholar 

  53. Gepstein, L. (2002). Derivation and potential applications of human embryonic stem cells. Circ Res, 91(10), 866–76.

    CAS  PubMed  Google Scholar 

  54. Darr, H., & Benvenisty, N. (2006). Human embryonic stem cells: the battle between self-renewal and differentiation. Regen Med, 1(3), 317–25.

    CAS  PubMed  Google Scholar 

  55. Friedrich Ben-Nun, I., & Benvenisty, N. (2006). Human embryonic stem cells as a cellular model for human disorders. Mol Cell Endocrinol, 252(1–2), 154–9.

    PubMed  Google Scholar 

  56. Ben-Yosef, D., Malcov, M., & Eiges, R. (2008). PGD-derived human embryonic stem cell lines as a powerful tool for the study of human genetic disorders. Mol Cell Endocrinol, 282(1–2), 153–8.

    CAS  PubMed  Google Scholar 

  57. Edwards, R. G. (2005). Ethics and moral philosophy in the initiation of IVF, preimplantation diagnosis and stem cells. Reprod Biomed Online, 10(Suppl 1), 1–8.

    PubMed  Google Scholar 

  58. Edwards, R. G. (2002). Personal pathways to embryonic stem cells. Reprod Biomed Online, 4(3), 263–78.

    CAS  PubMed  Google Scholar 

  59. Verlinsky, Y., Strelchenko, N., Kukharenko, V., Rechitsky, S., Verlinsky, O., Galat, V., et al. (2005). Human embryonic stem cell lines with genetic disorders. Reprod Biomed Online, 10(1), 105–10.

    CAS  PubMed  Google Scholar 

  60. Taei, A., Gourabi, H., Seifinejad, A., Totonchi, M., Shahbazi, E., Valojerdi, M. R., et al. (2010). Derivation of new human embryonic stem cell lines from preimplantation genetic screening and diagnosis-analyzed embryos. Vitro Cell Dev Biol Anim, 46(3–4), 395–402.

    Google Scholar 

  61. Jaroudi, S., & Wells, D. (2013). Microarray-CGH for the assessment of aneuploidy in human polar bodies and oocytes. Methods Mol Biol, 957, 267–83.

    CAS  PubMed  Google Scholar 

  62. Aran, B., Sole, M., Rodriguez-Piza, I., Parriego, M., Munoz, Y., Boada, M., et al. (2012). Vitrified blastocysts from Preimplantation Genetic Diagnosis (PGD) as a source for human Embryonic Stem Cell (hESC) derivation. J Assist Reprod Genet, 29(10), 1013–20.

    PubMed Central  PubMed  Google Scholar 

  63. Liu, Y., Li, Y., Hwang, A., Wang, S. Y., Jia, C. W., Yu, L., et al. (2011). Comparison of three embryo culture methods for derivation of human embryonic stem cells from discarded embryos. Cell Reprogram, 13(3), 233–9.

    CAS  PubMed  Google Scholar 

  64. Fan, Y., Luo, Y., Chen, X., & Sun, X. (2010). A modified culture medium increases blastocyst formation and the efficiency of human embryonic stem cell derivation from poor-quality embryos. J Reprod Dev, 56(5), 533–9.

    CAS  PubMed  Google Scholar 

  65. Meng, G., Liu, S., Li, X., Krawetz, R., & Rancourt, D. E. (2010). Derivation of human embryonic stem cell lines after blastocyst microsurgery. Biochem Cell Biol, 88(3), 479–90.

    CAS  PubMed  Google Scholar 

  66. Tropel, P., Tournois, J., Come, J., Varela, C., Moutou, C., Fragner, P., et al. (2010). High-efficiency derivation of human embryonic stem cell lines following pre-implantation genetic diagnosis. Vitro Cell Dev Biol Anim, 46(3–4), 376–85.

    Google Scholar 

  67. Ilic, D., Caceres, E., Lu, S., Julian, P., Foulk, R., & Krtolica, A. (2010). Effect of karyotype on successful human embryonic stem cell derivation. Stem Cells Dev, 19(1), 39–46.

    PubMed  Google Scholar 

  68. Menendez, P., Wang, L., & Bhatia, M. (2005). Genetic manipulation of human embryonic stem cells: a system to study early human development and potential therapeutic applications. Curr Gene Ther, 5(4), 375–85.

    CAS  PubMed  Google Scholar 

  69. Epsztejn-Litman, S., & Eiges, R. (2010). Genetic manipulation of human embryonic stem cells. Methods Mol Biol, 584, 387–411.

    CAS  PubMed  Google Scholar 

  70. Braam, S. R., Denning, C., & Mummery, C. L. (2010). Genetic manipulation of human embryonic stem cells in serum and feeder-free media. Methods Mol Biol, 584, 413–23.

    CAS  PubMed  Google Scholar 

  71. Li, M., Suzuki, K., Kim, N.Y., Liu, G.H., and Izpisua Belmonte, J.C. (2013). A cut above the rest: targeted genome editing technologies in human pluripotent stem cells. J Biol Chem.

  72. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–76.

    CAS  PubMed  Google Scholar 

  73. Kallur, T., Darsalia, V., Lindvall, O., & Kokaia, Z. (2006). Human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal rats. J Neurosci Res, 84(8), 1630–44.

    CAS  PubMed  Google Scholar 

  74. Kallur, T., Gisler, R., Lindvall, O., & Kokaia, Z. (2008). Pax6 promotes neurogenesis in human neural stem cells. Mol Cell Neurosci, 38(4), 616–28.

    CAS  PubMed  Google Scholar 

  75. Darbinyan, A., Kaminski, R., White, M. K., Darbinian, N., & Khalili, K. (2013). Isolation and propagation of primary human and rodent embryonic neural progenitor cells and cortical neurons. Methods Mol Biol, 1078, 45–54.

    PubMed Central  PubMed  Google Scholar 

  76. Chailangkarn, T., Acab, A., & Muotri, A. R. (2012). Modeling neurodevelopmental disorders using human neurons. Curr Opin Neurobiol, 22(5), 785–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Cundiff, P. E., & Anderson, S. A. (2011). Impact of induced pluripotent stem cells on the study of central nervous system disease. Curr Opin Genet Dev, 21(3), 354–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Wang, H., & Doering, L. C. (2012). Induced pluripotent stem cells to model and treat neurogenetic disorders. Neural Plast, 2012, 346053.

    PubMed Central  PubMed  Google Scholar 

  79. Elkabetz, Y., & Studer, L. (2008). Human ESC-derived neural rosettes and neural stem cell progression. Cold Spring Harb Symp Quant Biol, 73, 377–87.

    CAS  PubMed  Google Scholar 

  80. Telias, M., Segal, M., & Ben-Yosef, D. (2013). Neural differentiation of Fragile X human Embryonic Stem Cells reveals abnormal patterns of development despite successful neurogenesis. Dev Biol, 374(1), 32–45.

    CAS  PubMed  Google Scholar 

  81. Muguruma, K., & Sasai, Y. (2012). In vitro recapitulation of neural development using embryonic stem cells: from neurogenesis to histogenesis. Dev Growth Differ, 54(3), 349–57.

    CAS  PubMed  Google Scholar 

  82. Tornero, D., Wattananit, S., Gronning Madsen, M., Koch, P., Wood, J., Tatarishvili, J., et al. (2013). Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain.

  83. Tonnesen, J., Parish, C. L., Sorensen, A. T., Andersson, A., Lundberg, C., Deisseroth, K., et al. (2011). Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model. PLoS One, 6(3), e17560.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Badger, J.L., Cordero-Llana, O., Hartfield, E.M., and Wade-Martins, R. (2014). Parkinson’s disease in a dish - Using stem cells as a molecular tool. Neuropharmacology, 76 Pt A: p. 88–96.

  85. Deleidi, M., Cooper, O., Hargus, G., Levy, A., & Isacson, O. (2011). Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. PLoS One, 6(5), e19926.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Daadi, M. M. (2008). In vitro assays for neural stem cell differentiation: induction of dopaminergic phenotype. Methods Mol Biol, 438, 205–12.

    CAS  PubMed  Google Scholar 

  87. Mackay-Sim, A. (2013). Patient-derived stem cells: pathways to drug discovery for brain diseases. Front Cell Neurosci, 7, 29.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Boissart, C., Poulet, A., Georges, P., Darville, H., Julita, E., Delorme, R., et al. (2013). Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Transl Psychiatry, 3, e294.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T., & Eggan, K. (2007). Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci, 10(5), 608–14.

    PubMed Central  PubMed  Google Scholar 

  90. Grade, S., Bernardino, L., and Malva, J.O. (2013). Oligodendrogenesis from neural stem cells: Perspectives for remyelinating strategies. Int J Dev Neurosci.

  91. Izrael, M., Zhang, P., Kaufman, R., Shinder, V., Ella, R., Amit, M., et al. (2007). Human oligodendrocytes derived from embryonic stem cells: Effect of noggin on phenotypic differentiation in vitro and on myelination in vivo. Mol Cell Neurosci, 34(3), 310–23.

    CAS  PubMed  Google Scholar 

  92. Geschwind, D. H., & Levitt, P. (2007). Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol, 17(1), 103–11.

    CAS  PubMed  Google Scholar 

  93. Zwaigenbaum, L., Bryson, S., & Garon, N. (2013). Early identification of autism spectrum disorders. Behav Brain Res, 251, 133–46.

    PubMed  Google Scholar 

  94. Association, A.P., (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). American Psychiatric Association

  95. Huerta, M., Bishop, S. L., Duncan, A., Hus, V., & Lord, C. (2012). Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am J Psychiatry, 169(10), 1056–64.

    PubMed  Google Scholar 

  96. Rapin, I., & Tuchman, R. F. (2008). What is new in autism? Curr Opin Neurol, 21(2), 143–9.

    PubMed  Google Scholar 

  97. Santangelo, S. L., & Tsatsanis, K. (2005). What is known about autism: genes, brain, and behavior. Am J Pharmacogenomics, 5(2), 71–92.

    CAS  PubMed  Google Scholar 

  98. Piggot, J., Shirinyan, D., Shemmassian, S., Vazirian, S., & Alarcon, M. (2009). Neural systems approaches to the neurogenetics of autism spectrum disorders. Neuroscience, 164(1), 247–56.

    CAS  PubMed  Google Scholar 

  99. Jeste, S.S. and Geschwind, D.H. (2014). Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol.

  100. Autism, Developmental Disabilities Monitoring Network Surveillance Year Principal, I., Centers for Disease, C., and Prevention. (2009). Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ, 58(10), 1–20.

    Google Scholar 

  101. Van Wijngaarden-Cremers, P.J., van Eeten, E., Groen, W.B., Van Deurzen, P.A., Oosterling, I.J., and Van der Gaag, R.J. (2013). Gender and Age Differences in the Core Triad of Impairments in Autism Spectrum Disorders: A Systematic Review and Meta-analysis. J Autism Dev Disord.

  102. Lin, M., Pedrosa, E., Shah, A., Hrabovsky, A., Maqbool, S., Zheng, D., et al. (2011). RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One, 6(9), e23356.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Lin, M., Hrabovsky, A., Pedrosa, E., Wang, T., Zheng, D., & Lachman, H. M. (2012). Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. PLoS One, 7(8), e44017.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Stamou, M., Streifel, K. M., Goines, P. E., & Lein, P. J. (2013). Neuronal connectivity as a convergent target of gene x environment interactions that confer risk for Autism Spectrum Disorders. Neurotoxicol Teratol, 36, 3–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Chanda, S., Marro, S., Wernig, M., & Sudhof, T. C. (2013). Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation. Proc Natl Acad Sci U S A, 110(41), 16622–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. DeRosa, B. A., Van Baaren, J. M., Dubey, G. K., Lee, J. M., Cuccaro, M. L., Vance, J. M., et al. (2012). Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells. Neurosci Lett, 516(1), 9–14.

    CAS  PubMed  Google Scholar 

  107. Zeng, L., Zhang, P., Shi, L., Yamamoto, V., Lu, W., & Wang, K. (2013). Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. PLoS One, 8(3), e59685.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Gargus, J. J. (2006). Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry, 60(2), 177–85.

    CAS  PubMed  Google Scholar 

  109. Bader, P. L., Faizi, M., Kim, L. H., Owen, S. F., Tadross, M. R., Alfa, R. W., et al. (2011). Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A, 108(37), 15432–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Cohen-Kutner, M., Yahalom, Y., Trus, M., & Atlas, D. (2012). Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels. Sci Rep, 2, 366.

    PubMed Central  PubMed  Google Scholar 

  111. Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med, 17(12), 1657–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Yazawa, M., & Dolmetsch, R. E. (2013). Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res, 6(1), 1–9.

    PubMed Central  PubMed  Google Scholar 

  113. Krey, J. F., Pasca, S. P., Shcheglovitov, A., Yazawa, M., Schwemberger, R., Rasmusson, R., et al. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci, 16(2), 201–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Penagarikano, O., Mulle, J. G., & Warren, S. T. (2007). The pathophysiology of fragile x syndrome. Annu Rev Genomics Hum Genet, 8, 109–29.

    CAS  PubMed  Google Scholar 

  115. Budimirovic, D. B., & Kaufmann, W. E. (2011). What can we learn about autism from studying fragile X syndrome? Dev Neurosci, 33(5), 379–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Rinehart, N. J., Cornish, K. M., & Tonge, B. J. (2011). Gender differences in neurodevelopmental disorders: autism and fragile x syndrome. Curr Top Behav Neurosci, 8, 209–29.

    CAS  PubMed  Google Scholar 

  117. Hagerman, R. J. (2006). Lessons from fragile X regarding neurobiology, autism, and neurodegeneration. J Dev Behav Pediatr, 27(1), 63–74.

    PubMed  Google Scholar 

  118. Fernandez, E., Rajan, N., & Bagni, C. (2013). The FMRP regulon: from targets to disease convergence. Front Neurosci, 7, 191.

    PubMed Central  PubMed  Google Scholar 

  119. Loesch, D., & Hagerman, R. (2012). Unstable mutations in the FMR1 gene and the phenotypes. Adv Exp Med Biol, 769, 78–114.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. van Eyk, C. L., & Richards, R. I. (2012). Dynamic mutations: where are they now? Adv Exp Med Biol, 769, 55–77.

    PubMed  Google Scholar 

  121. Willemsen, R., Bontekoe, C. J., Severijnen, L. A., & Oostra, B. A. (2002). Timing of the absence of FMR1 expression in full mutation chorionic villi. Hum Genet, 110(6), 601–5.

    CAS  PubMed  Google Scholar 

  122. Abitbol, M., Menini, C., Delezoide, A. L., Rhyner, T., Vekemans, M., & Mallet, J. (1993). Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nat Genet, 4(2), 147–53.

    CAS  PubMed  Google Scholar 

  123. Hergersberg, M., Matsuo, K., Gassmann, M., Schaffner, W., Luscher, B., Rulicke, T., et al. (1995). Tissue-specific expression of a FMR1/beta-galactosidase fusion gene in transgenic mice. Hum Mol Genet, 4(3), 359–66.

    CAS  PubMed  Google Scholar 

  124. Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., et al. (2012). FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature, 492(7429), 382–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Jayaseelan, S., & Tenenbaum, S. A. (2012). Neurodevelopmental disorders: Signalling pathways of fragile X syndrome. Nature, 492(7429), 359–60.

    CAS  PubMed  Google Scholar 

  126. Sidorov, M. S., Auerbach, B. D., & Bear, M. F. (2013). Fragile X mental retardation protein and synaptic plasticity. Mol Brain, 6, 15.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Levenga, J., de Vrij, F. M., Buijsen, R. A., Li, T., Nieuwenhuizen, I. M., Pop, A., et al. (2011). Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice. Neurobiol Learn Mem, 95(4), 467–72.

    CAS  PubMed  Google Scholar 

  128. Ng, M. C., Yang, Y. L., & Lu, K. T. (2013). Behavioral and synaptic circuit features in a zebrafish model of fragile X syndrome. PLoS One, 8(3), e51456.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Friedman, S.H., Dani, N., Rushton, E., and Broadie, K. (2013). Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila. Dis Model Mech.

  130. Eiges, R., Urbach, A., Malcov, M., Frumkin, T., Schwartz, T., Amit, A., et al. (2007). Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell, 1(5), 568–77.

    CAS  PubMed  Google Scholar 

  131. Urbach, A., Bar-Nur, O., Daley, G. Q., & Benvenisty, N. (2010). Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell, 6(5), 407–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Sheridan, S. D., Theriault, K. M., Reis, S. A., Zhou, F., Madison, J. M., Daheron, L., et al. (2011). Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One, 6(10), e26203.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Bar-Nur, O., Caspi, I., & Benvenisty, N. (2012). Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. J Mol Cell Biol, 4(3), 180–3.

    PubMed  Google Scholar 

  134. Castren, M., Tervonen, T., Karkkainen, V., Heinonen, S., Castren, E., Larsson, K., et al. (2005). Altered differentiation of neural stem cells in fragile X syndrome. Proc Natl Acad Sci U S A, 102(49), 17834–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Alisch, R. S., Wang, T., Chopra, P., Visootsak, J., Conneely, K. N., & Warren, S. T. (2013). Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus. BMC Med Genet, 14, 18.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Hagerman, P. (2013). Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol, 126(1), 1–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Hagerman, R., & Hagerman, P. (2013). Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol, 12(8), 786–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Liu, J., Koscielska, K. A., Cao, Z., Hulsizer, S., Grace, N., Mitchell, G., et al. (2012). Signaling defects in iPSC-derived fragile X premutation neurons. Hum Mol Genet, 21(17), 3795–805.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Weng, S. M., Bailey, M. E., & Cobb, S. R. (2011). Rett syndrome: from bed to bench. Pediatr Neonatol, 52(6), 309–16.

    PubMed  Google Scholar 

  140. Na, E. S., Nelson, E. D., Kavalali, E. T., & Monteggia, L. M. (2013). The impact of MeCP2 loss- or gain-of-function on synaptic plasticity. Neuropsychopharmacology, 38(1), 212–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Guerrini, R., & Parrini, E. (2012). Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia, 53(12), 2067–78.

    CAS  PubMed  Google Scholar 

  142. Trappe, R., Laccone, F., Cobilanschi, J., Meins, M., Huppke, P., Hanefeld, F., et al. (2001). MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet, 68(5), 1093–101.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Williamson, S. L., & Christodoulou, J. (2006). Rett syndrome: new clinical and molecular insights. Eur J Hum Genet, 14(8), 896–903.

    CAS  PubMed  Google Scholar 

  144. Neul, J. L. (2012). The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues Clin Neurosci, 14(3), 253–62.

    PubMed Central  PubMed  Google Scholar 

  145. Percy, A. K. (2011). Rett syndrome: exploring the autism link. Arch Neurol, 68(8), 985–9.

    PubMed Central  PubMed  Google Scholar 

  146. Hotta, A., Cheung, A. Y., Farra, N., Vijayaragavan, K., Seguin, C. A., Draper, J. S., et al. (2009). Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nat Methods, 6(5), 370–6.

    CAS  PubMed  Google Scholar 

  147. Muotri, A. R., Marchetto, M. C., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., et al. (2010). L1 retrotransposition in neurons is modulated by MeCP2. Nature, 468(7322), 443–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Marchetto, M. C., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4), 527–39.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Studer, L. (2010). Neuroscience: Excessive mobility interrupted. Nature, 468(7322), 383–4.

    CAS  PubMed  Google Scholar 

  150. Walsh, R. M., & Hochedlinger, K. (2010). Modeling Rett syndrome with stem cells. Cell, 143(4), 499–500.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Di Stefano, B., Maffioletti, S. M., Gentner, B., Ungaro, F., Schira, G., Naldini, L., et al. (2011). A microRNA-based system for selecting and maintaining the pluripotent state in human induced pluripotent stem cells. Stem Cells, 29(11), 1684–95.

    PubMed  Google Scholar 

  152. Pomp, O., Dreesen, O., Leong, D. F., Meller-Pomp, O., Tan, T. T., Zhou, F., et al. (2011). Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell, 9(2), 156–65.

    CAS  PubMed  Google Scholar 

  153. Cheung, A. Y., Horvath, L. M., Grafodatskaya, D., Pasceri, P., Weksberg, R., Hotta, A., et al. (2011). Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet, 20(11), 2103–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Ananiev, G., Williams, E. C., Li, H., & Chang, Q. (2011). Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One, 6(9), e25255.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Kim, K. Y., Hysolli, E., & Park, I. H. (2011). Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc Natl Acad Sci U S A, 108(34), 14169–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Farra, N., Zhang, W. B., Pasceri, P., Eubanks, J. H., Salter, M. W., & Ellis, J. (2012). Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Mol Psychiatry, 17(12), 1261–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Larimore, J., Ryder, P. V., Kim, K. Y., Ambrose, L. A., Chapleau, C., Calfa, G., et al. (2013). MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. PLoS One, 8(6), e65069.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Amenduni, M., De Filippis, R., Cheung, A. Y., Disciglio, V., Epistolato, M. C., Ariani, F., et al. (2011). iPS cells to model CDKL5-related disorders. Eur J Hum Genet, 19(12), 1246–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Ricciardi, S., Ungaro, F., Hambrock, M., Rademacher, N., Stefanelli, G., Brambilla, D., et al. (2012). CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol, 14(9), 911–23.

    CAS  PubMed  Google Scholar 

  160. Opitz, J. M., & Gilbert-Barness, E. F. (1990). Reflections on the pathogenesis of Down syndrome. Am J Med Genet Suppl, 7, 38–51.

    CAS  PubMed  Google Scholar 

  161. Sturgeon, X., Le, T., Ahmed, M. M., & Gardiner, K. J. (2012). Pathways to cognitive deficits in Down syndrome. Prog Brain Res, 197, 73–100.

    CAS  PubMed  Google Scholar 

  162. Patterson, T., Rapsey, C. M., & Glue, P. (2013). Systematic review of cognitive development across childhood in Down syndrome: implications for treatment interventions. J Intellect Disabil Res, 57(4), 306–18.

    CAS  PubMed  Google Scholar 

  163. Lott, I. T. (2012). Neurological phenotypes for Down syndrome across the life span. Prog Brain Res, 197, 101–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Parker, S. E., Mai, C. T., Canfield, M. A., Rickard, R., Wang, Y., Meyer, R. E., et al. (2010). Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res A Clin Mol Teratol, 88(12), 1008–16.

    CAS  PubMed  Google Scholar 

  165. Weijerman, M. E., & de Winter, J. P. (2010). Clinical practice. The care of children with Down syndrome. Eur J Pediatr, 169(12), 1445–52.

    PubMed Central  PubMed  Google Scholar 

  166. Weksler, M. E., Szabo, P., Relkin, N. R., Reidenberg, M. M., Weksler, B. B., & Coppus, A. M. (2013). Alzheimer’s disease and Down’s syndrome: treating two paths to dementia. Autoimmun Rev, 12(6), 670–3.

    PubMed  Google Scholar 

  167. Cardenas, A. M., Ardiles, A. O., Barraza, N., Baez-Matus, X., & Caviedes, P. (2012). Role of tau protein in neuronal damage in Alzheimer’s disease and Down syndrome. Arch Med Res, 43(8), 645–54.

    CAS  PubMed  Google Scholar 

  168. Creau, N. (2012). Molecular and cellular alterations in Down syndrome: toward the identification of targets for therapeutics. Neural Plast, 2012, 171639.

    PubMed Central  PubMed  Google Scholar 

  169. Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O’Doherty, A., Lyle, R., et al. (2008). DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am J Hum Genet, 83(3), 388–400.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Hernandez, D., Mee, P. J., Martin, J. E., Tybulewicz, V. L., & Fisher, E. M. (1999). Transchromosomal mouse embryonic stem cell lines and chimeric mice that contain freely segregating segments of human chromosome 21. Hum Mol Genet, 8(5), 923–33.

    CAS  PubMed  Google Scholar 

  171. Doherty, A. M., & Fisher, E. M. (2003). Microcell-mediated chromosome transfer (MMCT): small cells with huge potential. Mamm Genome, 14(9), 583–92.

    PubMed  Google Scholar 

  172. Biancotti, J. C., Narwani, K., Buehler, N., Mandefro, B., Golan-Lev, T., Yanuka, O., et al. (2010). Human embryonic stem cells as models for aneuploid chromosomal syndromes. Stem Cells, 28(9), 1530–40.

    CAS  PubMed  Google Scholar 

  173. Mou, X., Wu, Y., Cao, H., Meng, Q., Wang, Q., & Sun, C. (2012). Generation of disease-specific induced pluripotent stem cells from patients with different karyotypes of Down syndrome. Stem Cell Res Ther, 3(2), 14.

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Chou, S. T., Byrska-Bishop, M., Tober, J. M., Yao, Y., Vandorn, D., Opalinska, J. B., et al. (2012). Trisomy 21-associated defects in human primitive hematopoiesis revealed through induced pluripotent stem cells. Proc Natl Acad Sci U S A, 109(43), 17573–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Maclean, G. A., Menne, T. F., Guo, G., Sanchez, D. J., Park, I. H., Daley, G. Q., et al. (2012). Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc Natl Acad Sci U S A, 109(43), 17567–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Li, L. B., Chang, K. H., Wang, P. R., Hirata, R. K., Papayannopoulou, T., & Russell, D. W. (2012). Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell, 11(5), 615–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Lu, H. E., Yang, Y. C., Chen, S. M., Su, H. L., Huang, P. C., Tsai, M. S., et al. (2013). Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from Trisomy 21 amniotic fluid cells. Exp Cell Res, 319(4), 498–505.

    CAS  PubMed  Google Scholar 

  178. Briggs, J. A., Sun, J., Shepherd, J., Ovchinnikov, D. A., Chung, T. L., Nayler, S. P., et al. (2013). Integration-free induced pluripotent stem cells model genetic and neural developmental features of down syndrome etiology. Stem Cells, 31(3), 467–78.

    CAS  PubMed  Google Scholar 

  179. Weick, J. P., Held, D. L., Bonadurer, G. F., 3rd, Doers, M. E., Liu, Y., Maguire, C., et al. (2013). Deficits in human trisomy 21 iPSCs and neurons. Proc Natl Acad Sci U S A, 110(24), 9962–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Jiang, J., **g, Y., Cost, G. J., Chiang, J. C., Kolpa, H. J., Cotton, A. M., et al. (2013). Translating dosage compensation to trisomy 21. Nature, 500(7462), 296–300.

    CAS  PubMed  Google Scholar 

  181. Shi, Y., Kirwan, P., Smith, J., MacLean, G., Orkin, S. H., & Livesey, F. J. (2012). A human stem cell model of early Alzheimer’s disease pathology in Down syndrome. Sci Transl Med, 4(124), 124ra29.

    PubMed  Google Scholar 

  182. Cassidy, S. B., Schwartz, S., Miller, J. L., & Driscoll, D. J. (2012). Prader-Willi syndrome. Genet Med, 14(1), 10–26.

    CAS  PubMed  Google Scholar 

  183. Kernohan, K. D., & Berube, N. G. (2010). Genetic and epigenetic dysregulation of imprinted genes in the brain. Epigenomics, 2(6), 743–63.

    CAS  PubMed  Google Scholar 

  184. Thibert, R. L., Larson, A. M., Hsieh, D. T., Raby, A. R., & Thiele, E. A. (2013). Neurologic manifestations of Angelman syndrome. Pediatr Neurol, 48(4), 271–9.

    PubMed  Google Scholar 

  185. Whittington, J., & Holland, A. (2010). Neurobehavioral phenotype in Prader-Willi syndrome. Am J Med Genet C Semin Med Genet, 154C(4), 438–47.

    PubMed  Google Scholar 

  186. Chamberlain, S. J., & Lalande, M. (2010). Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13. Neurobiol Dis, 39(1), 13–20.

    CAS  PubMed  Google Scholar 

  187. Yang, J., Cai, J., Zhang, Y., Wang, X., Li, W., Xu, J., et al. (2010). Induced pluripotent stem cells can be used to model the genomic imprinting disorder Prader-Willi syndrome. J Biol Chem, 285(51), 40303–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Chamberlain, S. J., Chen, P. F., Ng, K. Y., Bourgois-Rocha, F., Lemtiri-Chlieh, F., Levine, E. S., et al. (2010). Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc Natl Acad Sci U S A, 107(41), 17668–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Nyhan, W. L. (1997). The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis, 20(2), 171–8.

    CAS  PubMed  Google Scholar 

  190. **nah, H. A., Visser, J. E., Harris, J. C., Verdu, A., Larovere, L., Ceballos-Picot, I., et al. (2006). Delineation of the motor disorder of Lesch-Nyhan disease. Brain, 129(Pt 5), 1201–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Nyhan, W.L., O’Neill, J.P., **nah, H.A., and Harris, J.C., Lesch-Nyhan Syndrome, in GeneReviews, R.A. Pagon, et al., Editors. 1993: Seattle (WA).

  192. Visser, J. E., Bar, P. R., & **nah, H. A. (2000). Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev, 32(2–3), 449–75.

    CAS  PubMed  Google Scholar 

  193. Saito, Y., & Takashima, S. (2000). Neurotransmitter changes in the pathophysiology of Lesch-Nyhan syndrome. Brain Dev, 22(Suppl 1), S122–31.

    PubMed  Google Scholar 

  194. Chen, B.C., Balasubramaniam, S., McGown, I.N., O’Neill, J.P., Chng, G.S., Keng, W.T., et al. (2013). Treatment of Lesch-Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians, including a girl. Brain Dev.

  195. Kallay, K., Liptai, Z., Benyo, G., Kassa, C., Goda, V., Sinko, J., et al. (2012). Successful unrelated umbilical cord blood transplantation in Lesch-Nyhan syndrome. Metab Brain Dis, 27(2), 193–6.

    CAS  PubMed  Google Scholar 

  196. Visser, J. E., Schretlen, D. J., Bloem, B. R., & **nah, H. A. (2011). Levodopa is not a useful treatment for Lesch-Nyhan disease. Mov Disord, 26(4), 746–9.

    PubMed Central  PubMed  Google Scholar 

  197. Urbach, A., Schuldiner, M., & Benvenisty, N. (2004). Modeling for Lesch-Nyhan disease by gene targeting in human embryonic stem cells. Stem Cells, 22(4), 635–41.

    CAS  PubMed  Google Scholar 

  198. Park, I. H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., et al. (2008). Disease-specific induced pluripotent stem cells. Cell, 134(5), 877–86.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Khan, I. F., Hirata, R. K., Wang, P. R., Li, Y., Kho, J., Nelson, A., et al. (2010). Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Mol Ther, 18(6), 1192–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Mastrangelo, L., Kim, J. E., Miyanohara, A., Kang, T. H., & Friedmann, T. (2012). Purinergic signaling in human pluripotent stem cells is regulated by the housekee** gene encoding hypoxanthine guanine phosphoribosyltransferase. Proc Natl Acad Sci U S A, 109(9), 3377–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Mekhoubad, S., Bock, C., de Boer, A. S., Kiskinis, E., Meissner, A., & Eggan, K. (2012). Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell, 10(5), 595–609.

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Sidransky, E. (2012). Gaucher disease: insights from a rare Mendelian disorder. Discov Med, 14(77), 273–81.

    PubMed  Google Scholar 

  203. Grabowski, G. A. (2012). Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program, 2012, 13–8.

    PubMed  Google Scholar 

  204. Rosenbloom, B. E., & Weinreb, N. J. (2013). Gaucher disease: a comprehensive review. Crit Rev Oncog, 18(3), 163–75.

    PubMed  Google Scholar 

  205. Vitner, E. B., & Futerman, A. H. (2013). Neuronal forms of Gaucher disease. Handb Exp Pharmacol, 216, 405–19.

    CAS  PubMed  Google Scholar 

  206. Panicker, L. M., Miller, D., Park, T. S., Patel, B., Azevedo, J. L., Awad, O., et al. (2012). Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease. Proc Natl Acad Sci U S A, 109(44), 18054–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Tiscornia, G., Vivas, E. L., Matalonga, L., Berniakovich, I., Barragan Monasterio, M., Eguizabal, C., et al. (2013). Neuronopathic Gaucher’s disease: induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds. Hum Mol Genet, 22(4), 633–45.

    CAS  PubMed  Google Scholar 

  208. Byrne, J. A. (2008). Generation of isogenic pluripotent stem cells. Hum Mol Genet, 17(R1), 37–41.

    Google Scholar 

  209. Soldner, F., Laganiere, J., Cheng, A. W., Hockemeyer, D., Gao, Q., Alagappan, R., et al. (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell, 146(2), 318–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Conti, L., & Cattaneo, E. (2010). Neural stem cell systems: physiological players or in vitro entities? Nat Rev Neurosci, 11(3), 176–87.

    CAS  PubMed  Google Scholar 

  211. Chambers, S. M., Mica, Y., Studer, L., & Tomishima, M. J. (2011). Converting human pluripotent stem cells to neural tissue and neurons to model neurodegeneration. Methods Mol Biol, 793, 87–97.

    CAS  PubMed  Google Scholar 

  212. Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol, 27(3), 275–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  213. LaVaute, T. M., Yoo, Y. D., Pankratz, M. T., Weick, J. P., Gerstner, J. R., & Zhang, S. C. (2009). Regulation of neural specification from human embryonic stem cells by BMP and FGF. Stem Cells, 27(8), 1741–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Li, X. J., Hu, B. Y., Jones, S. A., Zhang, Y. S., Lavaute, T., Du, Z. W., et al. (2008). Directed differentiation of ventral spinal progenitors and motor neurons from human embryonic stem cells by small molecules. Stem Cells, 26(4), 886–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Johnson, M. A., Weick, J. P., Pearce, R. A., & Zhang, S. C. (2007). Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci, 27(12), 3069–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., et al. (2013). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron, 78(5), 785–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Kim, J. E., O’Sullivan, M. L., Sanchez, C. A., Hwang, M., Israel, M. A., Brennand, K., et al. (2011). Investigating synapse formation and function using human pluripotent stem cell-derived neurons. Proc Natl Acad Sci U S A, 108(7), 3005–10.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank Prof. Menahem Segal from the Department of Neurobiology at Weizmann Institute of Science, and Dr. Mira Malcov and Dr. Yael Kalma from the Wolfe PGD-Stem Cell Lab at Tel-Aviv Sourasky Medical Center, for critical reading of the manuscript. Esther Eshkol is thanked for editorial assistance. This study was supported by NNE-Teva scholarship (M. Telias) and Tel-Aviv Medical Center (D. Ben-Yosef).

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The authors declare no conflict of interest.

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  1. The Wolfe PGD-Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Michael Telias & Dalit Ben-Yosef

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  1. Michael Telias
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  2. Dalit Ben-Yosef
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Correspondence to Dalit Ben-Yosef.

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Telias, M., Ben-Yosef, D. Modeling Neurodevelopmental Disorders Using Human Pluripotent Stem Cells. Stem Cell Rev and Rep 10, 494–511 (2014). https://doi.org/10.1007/s12015-014-9507-2

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  • DOI: https://doi.org/10.1007/s12015-014-9507-2

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